Nogo-B inhibition facilitates cholesterol metabolism to reduce hypercholesterolemia
The strategy of lowering cholesterol levels by promoting cholesterol excretion is still lacking, and few molecular targets act on multiple cholesterol metabolic processes. In this study, we find that Nogo-B deficiency/inhibition simultaneously promotes hepatic uptake of cholesterol and cholesterol excretion. Nogo-B deficiency decreases cholesterol levels by activating ATP-binding cassette transporters (ABCs), apolipoprotein E (ApoE), and low-density lipoprotein receptor (LDLR) expression. We discover that Nogo-B interacts with liver X receptor α (LXRα), and Nogo-B deficiency inhibits ubiquitination degradation of LXRα, thereby enhancing its function on cholesterol excretion. Decreased cellular cholesterol levels further activate SREBP2 and LDLR expression, thereby promoting hepatic uptake of cholesterol. Nogo-B inhibition decreases atherosclerotic plaques and cholesterol levels in mice, and Nogo-B levels are correlated to cholesterol levels in human plasma. In this study, Nogo-B deficiency/inhibition not only promotes hepatic uptake of blood cholesterol but also facilitates cholesterol excretion. This study reports a strategy to lower cholesterol levels by inhibiting Nogo-B expression to promote hepatic cholesterol uptake and cholesterol excretion.
Authors
- Xiaoqiang Tang (ORCID: https://orcid.org/0000-0003-1314-3417)
- Yajun Duan (ORCID: https://orcid.org/0000-0002-3880-9070)
- Shasha Chen (ORCID: https://orcid.org/0000-0002-1446-7678)
- Ke Gong (ORCID: https://orcid.org/0000-0001-7025-4864)
- Zequn Yin
- Hou‐Zao Chen (ORCID: https://orcid.org/0000-0001-6805-3182)
- Miao Yu
- Yuanli Chen (ORCID: https://orcid.org/0000-0003-0813-3847)
- Mengyao Wang (ORCID: https://orcid.org/0000-0002-0420-8496)
- Yanfang Yang (ORCID: https://orcid.org/0000-0001-5214-7758)
- Likun Ma (ORCID: https://orcid.org/0000-0002-9680-1472)
- Zian Feng (ORCID: https://orcid.org/0000-0001-7780-2229)
- Dan Zhao (ORCID: https://orcid.org/0000-0002-5120-6725)
- Yasuko Iwakiri (ORCID: https://orcid.org/0000-0001-8032-5654)
- Tengteng Yan
- Shuang Zhang (ORCID: https://orcid.org/0000-0002-4076-9266)
- Jiaqi Li (ORCID: https://orcid.org/0000-0002-3187-5606)
- Liang Chen (ORCID: https://orcid.org/0000-0001-6374-112X)
- Xia Zhang (ORCID: https://orcid.org/0000-0002-7094-5654)
- Ke Feng (ORCID: https://orcid.org/0000-0003-4476-1939)
- Yingquan Liang
- Xiaoxiao Yang
- Peng Zeng (ORCID: https://orcid.org/0009-0002-2746-7156)
- Qian Li (ORCID: https://orcid.org/0000-0002-9919-4655)
- Chao Xue
Institutions
- University of Science and Technology of China (CN)
- Hefei University of Technology (CN)
- Anhui Medical University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Nankai University (CN)
- Sichuan University (CN)
- Yale University (US)
- Soochow University (CN)
- State Key Laboratory of Medicinal Chemical Biology
- State Key Laboratory of Biotherapy
- Tianjin Medical University (CN)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-09-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114691
- Citations
- 4
- Primary Topic
- Lipoproteins and Cardiovascular Health
- Type
- article
- Field-Weighted Citation Impact
- 2.29
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Anhui Province